PROJECT SUMMARY/ABSTRACT Alcohol use disorders (AUDs; alcohol abuse and dependence) and problematic alcohol use are associated with substantial negative outcomes and significant impairment in multiple domains of functioning, including physical health and mortality, psychiatric health, psychosocial functioning, neurocognitive deficits, and deviations in brain structure and functioning. However, the primarily cross-sectional nature of the vast majority of existing research means that the causal basis of these associations remains unclear?problematic alcohol use appears to have neurotoxic effects on the brain, but it is also plausible that brain deviations reflect pre- existing liability toward problematic alcohol use in the first place. The proposed secondary data analysis award aims to address this question by leveraging alcohol use and magnetic resonance imaging (MRI) data already collected in two large, independent, population-based, genetically informative adult samples from the Minnesota Center for Twin and Family Research (MCTFR, N = 1152) and the Human Connectome Project (HCP, N = 1113). Specific Aim 1 is to conduct a comprehensive, meta-analytic synthesis of the existing empirical literature to quantify associations between varied indicators of alcohol use and brain morphometry; we expect to find modest-to-moderate population effects for brain structure and white matter microstructure deviations in systems underlying inhibitory control, reward processing, and learning/memory. Specific Aim 2 follows up on the results of the meta-analysis by applying sophisticated and innovative quantitative methods in the MCTFR sample of twins to get at issues of causality, including co-twin analyses that differentiate pre- existing liability from exposure-related effects of alcohol on the brain, biometric modeling to partition shared familial liability into genetic and shared environmental effects, and propensity score adjustment to control for confounding factors unshared by co-twins; we hypothesize that brain deviations underlying impaired inhibitory control and reward processing reflect pre-existing liability, whereas deviations underlying impaired learning/memory reflect alcohol exposure-related effects. The inclusion of a much larger sample of females than typically examined in alcohol research further allows us to examine potential moderation by sex in Specific Aim 3, specifically the hypothesis that the female brain is more susceptible than the male brain to effects of alcohol exposure. Finally, Specific Aim 4 is a replication attempt of positive findings in the independent HCP sample of twins and their nontwin siblings. Thus, the proposed project combines several strategies to ensure credible, causally informative, generalizable, and reproducible findings. Results have considerable potential to further understanding of the etiology and consequences of problematic alcohol use, and, in turn, guide needed prevention and intervention efforts to reduce the tremendous negative public health and personal implications of alcohol misuse.